Title : Structural Insights into the Niemann-Pick C1 (
NPC1 )-Mediated Cholesterol Transfer and Ebola Infection
Abstract :
- Niemann-Pick disease type C (NPC ) is associated with mutations in NPC1 and NPC2 , whose gene products are key players in the endosomal/lysosomal egress of low-density lipoprotein-derived cholesterol
- NPC1 is also the intracellular receptor for Ebola virus (EBOV)
- Here, we present a 4.4 Å structure of full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein ( GPcl ) of EBOV, both determined by single-particle electron cryomicroscopy
- NPC1 contains 13 transmembrane segments (TMs) and three distinct lumenal domains A (also designated NTD ), C, and I. TMs 2-13 exhibit a typical resistance-nodulation-cell division fold, among which TMs 3-7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling
- A trimeric EBOV- GPcl binds to one NPC1 monomer through the domain C
- Our structural and biochemical characterizations provide an important framework for mechanistic understanding of NPC1-mediated intracellular cholesterol trafficking and Ebola virus infection